Preserved Efficacy and Reduced Toxicity with Intermittent Linezolid Dosing in Combination with Bedaquiline and Pretomanid in a Murine Tuberculosis Model.

Antimicrobial Agents and Chemotherapy
K. M. BigelowEric L Nuermberger

Abstract

The novel regimen of bedaquiline, pretomanid, and linezolid (BPaL) is highly effective against drug-resistant tuberculosis, but linezolid toxicities are frequent. We hypothesized that, for a similar total weekly cumulative dose, thrice-weekly administration of linezolid would preserve efficacy while reducing toxicity compared with daily dosing, in the context of the BPaL regimen. Using C3HeB/FeJ and BALB/c mouse models of tuberculosis disease, thrice-weekly linezolid dosing was compared with daily dosing, with intermittent dosing introduced (i) from treatment initiation or (ii) after an initial period of daily dosing. In all animals, BPa was dosed daily throughout treatment. Blood counts were used to assess hematologic toxicity. After unexpected findings of apparent antagonism, we conducted additional experiments to investigate strain-to-strain differences in the contribution of linezolid to regimen efficacy by comparing each 1- and 2-drug component to the BPaL regimen in BALB/c mice infected with Mycobacterium tuberculosis H37Rv or HN878. Giving linezolid daily for 1 to 2 months achieved the greatest efficacy but, after that, results were similar if the drug was stopped, dosed thrice-weekly, or continued daily. Erythrocyte cou...Continue Reading

References

Jun 14, 2003·The Journal of Antimicrobial Chemotherapy·F C Odds
May 27, 2005·Antimicrobial Agents and Chemotherapy·Sandeep TyagiJ Grosset
Jan 3, 2006·Proceedings of the National Academy of Sciences of the United States of America·Ujjini H ManjunathaClifton E Barry
May 26, 2006·Antimicrobial Agents and Chemotherapy·E E McKeeT A Marks
Sep 24, 2008·Seminars in Respiratory and Critical Care Medicine·Eric Nuermberger
Jun 13, 2009·American Journal of Respiratory and Critical Care Medicine·Kathy N WilliamsEric L Nuermberger
Jul 22, 2009·Antimicrobial Agents and Chemotherapy·Deepak AlmeidaJacques Grosset
Feb 4, 2010·The Journal of Antimicrobial Chemotherapy·Zahoor AhmadPetros C Karakousis
Oct 13, 2010·Antimicrobial Agents and Chemotherapy·Zahoor AhmadEric L Nuermberger
Sep 21, 2011·Antimicrobial Agents and Chemotherapy·Rokeya TasneenEric L Nuermberger
Dec 27, 2011·The Journal of Infectious Diseases·Jamie HarperSanjay K Jain
May 4, 2012·The Journal of Antimicrobial Chemotherapy·Federico PeaMario Furlanut
Oct 19, 2012·The New England Journal of Medicine·Myungsun LeeClifton E Barry
Apr 9, 2013·International Journal of Antimicrobial Agents·Dario CattaneoEmilio Clementi
May 8, 2013·Antimicrobial Agents and Chemotherapy·Kwok-Chiu ChangRaphael Chiu-Yeung Chan
Feb 4, 2014·Nature Reviews. Microbiology·Véronique Dartois
Jul 11, 2014·PloS One·Koen AndriesAnil Koul
Sep 27, 2014·Cold Spring Harbor Perspectives in Medicine·Andrea M Cooper
Oct 22, 2014·Antimicrobial Agents and Chemotherapy·Shawn FlanaganPhilippe Prokocimer
Jun 4, 2015·Disease Models & Mechanisms·Jean-Philippe LanoixEric L Nuermberger
Jul 16, 2015·The New England Journal of Medicine·Myungsun LeeIna Jeong
May 18, 2016·Antimicrobial Agents and Chemotherapy·Deepak AlmeidaEric Nuermberger
Aug 3, 2016·Disease Models & Mechanisms·Alvaro A OrdonezSanjay K Jain
Aug 18, 2016·Expert Review of Anti-infective Therapy·Sean WassermanGary Maartens
Oct 16, 2016·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Devyani DeshpandeTawanda Gumbo
Feb 28, 2017·The International Journal of Tuberculosis and Lung Disease : the Official Journal of the International Union Against Tuberculosis and Lung Disease·E Nuermberger
Jun 7, 2017·Antimicrobial Agents and Chemotherapy·Shashikant SrivastavaTawanda Gumbo
Mar 11, 2018·Tuberculosis·Mamoru FujiwaraMakoto Matsumoto
Jan 30, 2020·The Journal of Infectious Diseases·Kristina M BigelowEric L Nuermberger
Mar 5, 2020·The New England Journal of Medicine·Francesca ConradieUNKNOWN Nix-TB Trial Team

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Citations

Mar 19, 2021·The Journal of Antimicrobial Chemotherapy·Hannah Yejin KimJan-Willem Alffenaar
May 7, 2021·The Journal of Membrane Biology·Ameya D BendreJanesh Kumar
Jun 13, 2021·European Journal of Medicinal Chemistry·Yashodeep ShindeHarun Patel
Sep 21, 2021·Antimicrobial Agents and Chemotherapy·Mahmoud Tareq AbdelwahabPaolo Denti

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